April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Molecular Mechanism of PAX2/Pax2 Missense Mutations in Mouse and Human
B. P. Brooks; V. Camasamudram; F. Onojafe; Y. Sergeev; E. Boobalan; K. Tang; H. Liu; C.-H. Xia; X. Gong; R. Alur
Author Affiliations & Notes
  • B. P. Brooks
    Ophthalmic Genetics Branch, National Eye Inst/NIH, Bethesda, Maryland
  • V. Camasamudram
    NIDCD/NIH, Bethesda, Maryland
  • F. Onojafe
    Ophthalmic Genetics Branch, National Eye Inst/NIH, Bethesda, Maryland
  • Y. Sergeev
    Ophthalmic Genetics Branch, National Eye Inst/NIH, Bethesda, Maryland
  • E. Boobalan
    Ophthalmic Genetics Branch, National Eye Inst/NIH, Bethesda, Maryland
  • K. Tang
    Dept. of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas
  • H. Liu
    School of Optometry and Vision Science Program, University of California, Berkeley, California
  • C.-H. Xia
    School of Optometry and Vision Science Program, University of California, Berkeley, California
  • X. Gong
    School of Optometry and Vision Science Program, University of California, Berkeley, California
  • R. Alur
    Ophthalmic Genetics Branch, National Eye Inst/NIH, Bethesda, Maryland
  • Footnotes
    Commercial Relationships  B.P. Brooks, None; V. Camasamudram, None; F. Onojafe, None; Y. Sergeev, None; E. Boobalan, None; K. Tang, None; H. Liu, None; C.-H. Xia, None; X. Gong, None; R. Alur, None.
  • Footnotes
    Support  This work was supported by the intramural program at the National Eye Institute, National Institutes of Health, and by NIH grant EY013849.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 2603. doi:
  • Views
  • Share
  • Tools
    • Alerts
      User Alerts
      You are adding an alert for:
      Molecular Mechanism of PAX2/Pax2 Missense Mutations in Mouse and Human
      You will receive an email whenever this article is corrected, updated, or cited in the literature. You can manage this and all other alerts in My Account
      The alert will be sent to:
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation
      Citation

      B. P. Brooks, V. Camasamudram, F. Onojafe, Y. Sergeev, E. Boobalan, K. Tang, H. Liu, C.-H. Xia, X. Gong, R. Alur; Molecular Mechanism of PAX2/Pax2 Missense Mutations in Mouse and Human. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2603.

      Download citation file:

      © ARVO (1962-2015); The Authors (2016-present)

      ×
    • Get Permissions
  • Supplements
Abstract

Purpose: : PAX2

Methods: : The murine Pax2 mutation was identified using standard genetic mapping and DNA sequencing. Heterozygous & homozygous mutant embryos/mice were comprehensively phenotyped. Analysis of structural changes of Pax2/PAX2 due tomutations was performed in silico. In vitro measurements of wild-type and mutant Pax2 protein and mRNA expression, transactivation, sub-cellular localization, DNA binding & protein stability were examined.

Results: : A p.T74A mutation in Pax2 leads to developmental ocular and kidney, but not midbrain, abnormalities, similar to previously-reported in knock-out mouse models & humans with PRS. This mutation, along with the two other mutations reported in humans, (p.G75S and p.dup73ET) is predicted to disrupt critical hydrogen bonds in the Pax2 homeodomain. All 3 mutations lead to decreased steady-state levels of Pax2 protein in vitro & a commensurate decrease in transactivation, but do not affect protein localization or DNA binding. The reduction in steady-state protein levels is not due to mRNA stability.

Conclusions: : Reduced Pax2/PAX2 protein stability is the molecular mechanism responsible for the PRS phenotype caused by the characterized missense mutations. Our murine model will enable us to investigate how mutant Pax2 protein interacts with other components of the transcriptional apparatus.

Keywords: genetics • transcription factors • optic nerve 
© 2010, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Permission to republish any abstract or part of an abstract in any form must be obtained in writing from the ARVO Office prior to publication.
Copyright © 2024 Association for Research in Vision and Ophthalmology.
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×
This site uses cookies. By continuing to use our website, you are agreeing to our privacy policy.Accept